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1.
Cell Transplant ; 30: 9636897211054481, 2021.
Article in English | MEDLINE | ID: covidwho-1511642

ABSTRACT

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Interleukin-6/biosynthesis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , Cells, Cultured , Coculture Techniques , Combined Modality Therapy , DNA, Complementary/genetics , Gene Expression Regulation/drug effects , Humans , Inflammation , Interleukin-6/genetics , Interleukin-6/pharmacology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation/drug effects , Phytohemagglutinins/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/biosynthesis , Receptors, Interleukin-6/genetics , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Umbilical Cord/cytology
3.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1437669

ABSTRACT

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Basigin/antagonists & inhibitors , Basigin/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , COVID-19/genetics , Chlorocebus aethiops , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells
4.
J Infect Dis ; 224(6): 934-937, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1429244

ABSTRACT

Emerging data from open-label randomized trials without placebo controls suggest potential mortality benefits for combining corticosteroids with the interleukin 6 receptor antagonist tocilizumab in severe coronavirus disease 2019. Conversely, dual immunomodulation may weaken antiviral responses and delay viral clearance, allowing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to expand its population and accrue genetic diversity within individual hosts. Generating a pool of hosts with genetically diverse viral populations while introducing new selective pressures in the form of vaccination-induced immunity could accelerate the process of antigenic drift in SARS-CoV-2. However, clinical trials to date have largely disregarded viral outcomes, and data on viral kinetics in response to immunomodulation are scarce. Coadministration of antiviral agents with immunomodulation could serve as a potential strategy to aid viral clearance and reduce the risk of genetic diversification.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , COVID-19/drug therapy , Dexamethasone/pharmacology , SARS-CoV-2/drug effects , Adrenal Cortex Hormones/pharmacology , Antiviral Agents/pharmacology , Drug Combinations , Humans , Immunologic Factors
6.
Biochem Biophys Res Commun ; 578: 91-96, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1401240

ABSTRACT

The SARS-CoV-2 variant is rapidly spreading across the world and causes to resurge infections. We previously reported that CT-P59 presented its in vivo potency against Beta variants, despite its reduced activity in cell experiments. Yet, it remains uncertain to exert the antiviral effect of CT-P59 on Gamma, Delta and its associated variants (L452R). To tackle this question, we carried out cell tests and animal studies. CT-P59 showed neutralization against Gamma, Delta, Epsilon, and Kappa variants in cells, with reduced susceptibility. The mouse challenge experiments with Gamma and Delta variants substantiated in vivo potency of CT-P59 showing symptom remission and virus abrogation in the respiratory tract. Collectively, cell and animal studies showed that CT-P59 is effective against Gamma and Delta variants infection, hinting that CT-P59 has therapeutic potential for patients infected with Gamma, Delta and its associated variants.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/pharmacology , COVID-19/drug therapy , Disease Models, Animal , Immunoglobulin G/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/pharmacology , Body Weight/drug effects , COVID-19/virology , Female , Humans , Mice, Transgenic , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Survival Analysis
7.
Pharmacol Rep ; 73(6): 1520-1538, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1377631

ABSTRACT

The global spread of COVID-19 has imparted significant economic, medical, and social burdens. Like adults, children are affected by this pandemic. However, milder clinical symptoms are often experienced by them. Only a minimal proportion of the affected patients may develop severe and complicated COVID-19. Supportive treatment is recommended in all patients. Antiviral and immunomodulatory medications are spared for hospitalized children with respiratory distress or severe to critical disease. Up till now, remdesivir is the only USFDA-approved anti-COVID-19 medication indicated in the majority of symptomatic patients with moderate to severe disease. Dexamethasone is solely recommended in patients with respiratory distress maintained on oxygen or ventilatory support. The use of these medications in pediatric patients is founded on evidence deriving from adult studies. No randomized controlled trials (RCTs) involving pediatric COVID-19 patients have assessed these medications' efficacy and safety, among others. Similarly, three novel monoclonal anti-SARS-CoV-2 spike protein antibodies, bamlanivimab, casirivimab and imdevimab, have been recently authorized by the USFDA. Nonetheless, their efficacy has not been demonstrated by multiple RCTs. In this review, we aim to dissect the various potential therapeutics used in children with COVID-19. We aspire to provide a comprehensive review of the available evidence and display the mechanisms of action and the pharmacokinetic properties of the studied therapeutics. Our review offers an efficient and practical guide for treating children with COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Azithromycin/pharmacology , Child , Dexamethasone/pharmacology , Humans , Hydroxychloroquine/pharmacology , Ivermectin/pharmacology , Lopinavir/pharmacology , Oseltamivir/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
8.
PLoS One ; 16(8): e0255976, 2021.
Article in English | MEDLINE | ID: covidwho-1365424

ABSTRACT

BACKGROUND: Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. AIMS AND METHODS: We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1ß antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. RESULTS: Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. CONCLUSION: Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Arrhythmias, Cardiac , COVID-19 , Calcium Signaling/drug effects , Myocytes, Cardiac , SARS-CoV-2/metabolism , Adult , Aged , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/pathology , COVID-19/complications , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , Calcium/metabolism , Drug Evaluation, Preclinical , Female , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Male , Middle Aged , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats , Rats, Sprague-Dawley , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/metabolism , Ventricular Dysfunction, Left/pathology
10.
Ann Clin Transl Neurol ; 8(8): 1738-1744, 2021 08.
Article in English | MEDLINE | ID: covidwho-1300348

ABSTRACT

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , COVID-19/physiopathology , Immunologic Factors/pharmacology , Interferons/pharmacology , Multiple Sclerosis/drug therapy , Rituximab/pharmacology , Adult , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/epidemiology , Female , France/epidemiology , Humans , Immunologic Factors/adverse effects , Interferons/adverse effects , Italy/epidemiology , Male , Meta-Analysis as Topic , Middle Aged , Multiple Sclerosis/epidemiology , Multivariate Analysis , Protective Factors , Retrospective Studies , Risk Factors , Rituximab/adverse effects , Severity of Illness Index
11.
Lancet Respir Med ; 9(6): 643-654, 2021 06.
Article in English | MEDLINE | ID: covidwho-1291133

ABSTRACT

Circulating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological and anti-inflammatory functions. An adequate understanding of the complex processes by which IL-6 signalling occurs is crucial for the correct interpretation of IL-6 concentrations in the blood or lung, the use of IL-6 as a critical care biomarker, or the design of effective anti-IL-6 strategies. Here, we outline the role of IL-6 in health and disease, explain the different types of IL-6 signalling and their contribution to the net biological effect of the cytokine, describe the approaches to IL-6 inhibition that are currently available, and discuss implications for the future use of treatments such as tocilizumab in the critical care setting.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Interleukin-6 , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Biomarkers/blood , COVID-19/immunology , COVID-19/physiopathology , COVID-19/therapy , Critical Illness , Humans , Immunologic Factors/immunology , Immunologic Factors/pharmacology , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Interleukin-6/immunology , SARS-CoV-2
13.
Cell Rep ; 36(3): 109415, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1283976

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.


Subject(s)
Angiotensin-Converting Enzyme 2/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Viral/pharmacology , COVID-19/drug therapy , Esters/pharmacology , Guanidines/pharmacology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Cell Line , Humans , Protease Inhibitors/pharmacology , Protein Binding , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccination
14.
Indian J Pharmacol ; 53(3): 226-228, 2021.
Article in English | MEDLINE | ID: covidwho-1282691

ABSTRACT

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/pharmacology , Antirheumatic Agents/pharmacology , Antirheumatic Agents/therapeutic use , COVID-19/epidemiology , COVID-19/immunology , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/immunology , Disease Progression , Drug Resistance, Viral , Humans , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukins/antagonists & inhibitors , Interleukins/immunology , Janus Kinase Inhibitors/pharmacology , Recurrence
15.
Lung ; 199(3): 239-248, 2021 06.
Article in English | MEDLINE | ID: covidwho-1245631

ABSTRACT

BACKGROUND: To date, only dexamethasone has been shown to reduce mortality in coronavirus disease-19 (COVID-19) patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remain conflicting. STUDY DESIGN AND METHODS: Electronic databases such as MEDLINE, EMBASE, and Cochrane central were searched from March 1, 2020, until March 10, 2021, for randomized controlled trials evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were all-cause mortality, mechanical ventilation, and time to discharge. RESULTS: Nine studies (with 6490 patients) were included in the analysis. In total, 3358 patients received tocilizumab, and 3132 received standard care/placebo. Pooled analysis showed a significantly decreased risk of all-cause mortality (RR 0.89, 95% CI 0.80-0.98, p = 0.02) and progression to mechanical ventilation (RR 0.80, 95% CI 0.71-0.89, p < 0.0001) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.28, 95% CI 1.12-1.45, p = 0.0002). CONCLUSIONS: Tocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , COVID-19 , Receptors, Interleukin-6/antagonists & inhibitors , COVID-19/drug therapy , COVID-19/immunology , COVID-19/mortality , Humans , Immunologic Factors/pharmacology , Outcome Assessment, Health Care , SARS-CoV-2
16.
Sci Rep ; 11(1): 10220, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1228272

ABSTRACT

The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , COVID-19/drug therapy , Drug Repositioning , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , COVID-19/immunology , Drug Repositioning/methods , Epitopes/immunology , Humans , Ipilimumab/immunology , Ipilimumab/pharmacology , Molecular Docking Simulation , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
17.
Lancet Respir Med ; 9(6): 655-664, 2021 06.
Article in English | MEDLINE | ID: covidwho-1209411

ABSTRACT

The pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. In this Series paper, we review the clinical and methodological heterogeneity of studies of IL-6 receptor antagonists, and consider how this heterogeneity might have influenced reported treatment effects. Timing from clinical presentation to treatment, severity of illness, and concomitant use of corticosteroids are among the factors that might have contributed to apparently inconsistent results. With an understanding of the sources of variability in these trials, available evidence could be applied to guide clinical decision making and to inform the enrichment of future studies.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , COVID-19 , Clinical Trials as Topic , Receptors, Interleukin-6/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/immunology , COVID-19/immunology , COVID-19/therapy , Clinical Trials as Topic/methods , Clinical Trials as Topic/statistics & numerical data , Humans , Patient Selection , Receptors, Interleukin-6/immunology , SARS-CoV-2
18.
Expert Rev Med Devices ; 18(5): 457-471, 2021 May.
Article in English | MEDLINE | ID: covidwho-1174812

ABSTRACT

Introduction: The use of mechanical ventilation associated with acute hypoxemic respiratory failure, the most common complication in critically ill COVID-19 patients, defines a high risk population that requires specific consideration of outcomes and treatment practices.Areas covered: This review evaluates existing information about mortality rates and effectiveness of antiviral, immune-modulating, and anticoagulation treatments in COVID-19 patients who received mechanical ventilation. The mortality rate and follow-up periods in patients receiving mechanical ventilation ranged widely. Antivirals, including remdesivir and convalescent plasma, have shown no definitive mortality benefit in this population despite positive results in other COVID-19 patients. Dexamethasone was associated with an absolute reduction in 28-day mortality by 12.3% (95% CI, 6.3 to 17.6), after adjusting for age. Reduced mortality has been demonstrated with tocilizumab use alongside corticosteroids. Evidence is inconclusive for therapeutic anticoagulation, and further studies are needed to determine the comparative benefit of prophylactic anticoagulation.Expert opinion: Significant variation and high mortality rates in mechanically ventilated patients necessitate more standardized outcome measurements, increased consideration of risk factors to reduce intubation, and improved treatment practices. Anticoagulation and dexamethasone should be incorporated in the treatment of patients receiving invasive mechanical ventilation, while more rigorous studies are required for other potential treatments.


Subject(s)
COVID-19/mortality , Respiration, Artificial/mortality , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/therapy , COVID-19/virology , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Treatment Outcome
19.
Expert Opin Biol Ther ; 21(5): 675-686, 2021 05.
Article in English | MEDLINE | ID: covidwho-1174795

ABSTRACT

Objective: Efficacy and safety of Itolizumab, an immunomodulatory mAb, in treating moderate-to-severe acute respiratory distress syndrome (ARDS) due to cytokine release in COVID-19 patients was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase-2 study.Methods: Patients were randomized (2:1) to Arm-A (best supportive care [BSC]+Itolizumab) and Arm-B (BSC). Primary outcome of interest was reduction in mortality 30-days after enrollment.Results: Thirty-six patients were screened, five treated as first-dose-sentinels and rest randomized, while four patients were screen-failures. Two patients in Arm-A discontinued prior to receiving one complete infusion and were replaced. At end of 1-month, there were three deaths in Arm-B, and none in Arm-A (p = 0.0296; 95% CI = -0.3 [-0.61, -0.08]). At end of study, more patients in Arm-A had improved SpO2 without increasing FiO2 (p = 0.0296), improved PaO2 (p = 0.0296), and reduction in IL-6 (43 vs 212 pg/ml; p = 0.0296) and tumor necrotic factor-α (9 vs 39 pg/ml; p = 0.0253) levels. Transient lymphopenia (Arm-A: 11 patients) and infusion reactions (7 patients) were commonly reported treatment-related safety events.Conclusion: Itolizumab is a promising, safe and effective immunomodulatory therapy for treatment of ARDS due to cytokine release in COVID-19 patients, with survival and recovery-benefit.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Immunologic Factors/therapeutic use , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/drug effects , Severity of Illness Index , Adult , Antibodies, Monoclonal, Humanized/pharmacology , COVID-19/complications , COVID-19/immunology , Female , Humans , Immunologic Factors/pharmacology , Male , Middle Aged , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Treatment Outcome
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